Current Chemical Biology - Volume 17, Issue 4, 2023

Background: As per the Warburg effect, cancer cells are known to convert pyruvate into lactate. The accumulation of lactate is associated with metabolic and epigenetic reprogramming, which has newly been suggested to involve lactylation. However, the role of secreted lactate in modulating the tumor microenvironment through lactylation remains unclear. Specifically, there are gaps in our understanding of the enzyme responsible for converting lactate to lactyl-CoA and the nature of the enzyme that performs lactylation by utilizing lactyl-CoA as a substrate. It is worth noting that there are limited papers focused on metabolite profiling that detect lactate and lactyl-CoA levels intracellularly and extracellularly in the context of cancer cells. Methods: Here, we have employed an in-house developed vertical tube gel electrophoresis (VTGE) and LC-HRMS assisted profiling of extracellular metabolites of breast cancer cells treated by anticancer compositions of cow urine DMSO fraction (CUDF) that was reported previously. Furthermore, we used molecular docking and molecular dynamics (MD) simulations to determine the potential enzyme that can convert lactate to lactyl-CoA. Next, the histone acetyltransferase p300 (HAT p300) enzyme (PDB ID: 6GYR) was evaluated as a potential enzyme that can bind to lactyl- CoA during the lactylation process. Results: We collected evidence on the secretion of lactate in the extracellular conditioned medium of breast cancer cells treated by anticancer compositions. MD simulations data projected that acetyl- CoA synthetase could be a potential enzyme that may convert lactate into lactyl-CoA similar to a known substrate acetate. Furthermore, a specific and efficient binding (docking energy -9.6 kcal/mol) of lactyl-CoA with p300 HAT suggested that lactyl-CoA may serve as a substrate for lactylation similar to acetylation that uses acetyl-CoA as a substrate. Conclusion: In conclusion, our data provide a hint on the missing link for the lactylation process due to lactate in terms of a potential enzyme that can convert lactate into lactyl-CoA. This study helped us to project the HAT p300 enzyme that may use lactyl-CoA as a substrate in the lactylation process of the tumor microenvironment.

Background: Prickly pear "Opuntia ficus indica (L.) Mill. "otherwise known as the Indian fig tree, belongs to the family Cactaceae, and was known as a medicinal plant for its rich source of bioactive substances. Objective: The present work aims to promote prickly pear seeds for traditional therapy by phenolic profiling and pharmacological tests of aqueous extract. Method: An analytical quantification was performed by UV-Visible, and the identification of different bioactive compounds was done by HPLC-DAD. For pharmacological screening, an in vivo evaluation of the various tests, neuroleptic activity which consists of testing the recovery reflex; catatonic activity which is a test to detect catalepsy that can be characterized in animals by the administration of neuroleptic drugs; and for hypoglycemic activity a test was performed to assess glucose tolerance. Results: The administration of aqueous extract of the prickly pear seeds at a dose (400 mg/kg) allows a reduction in blood sugar with a maximum decrease of one and a half hours compared to the control group. Conclusion: This work makes it possible to postulate that the extract of prickly pear seeds is associated with a very interesting antihyperglycemic activity given its high content of phenolic compounds.

Background: Seafood is an important source of food for the majority of people. Marine species have a wide spectrum of pharmacological actions, including antibacterial, antiviral, antiparasitic, anti-inflammatory, and anti-diabetic properties. Objective: The purpose of this study was to examine the effects of Sepia officinalis extract (SoE) on folic acid-induced acute kidney injury in Wistar rats. Methods: A single dosage of folic acid (250 mg/kg) was injected intraperitoneally to cause kidney injury induced (AKI). The study contained three groups of six rats each: control, folic acid, and folic acid + SoE groups. The SoE group received SoE (45 mg/kg, orally) daily for one week, while the control and folic acid groups were administered distilled water. Results: The crude extract of Sepia officianlis contains heavy metals such as Fe, Cr, Cd, Pb, and Zn, according to our findings. The LD50 value of SoE was 450 mg/kg. SoE treatment increases creatinine, urea, uric acid, sodium, potassium, chloride, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyltransferase, malondialdehyde, and nitric oxide levels while decreasing total proteins, albumin, glutathione reduced, glutathione-S-transferase, and catalase. Several histological alterations were found in the liver and kidney of the SoE rats. Conclusion: The heavy metal content of S. officinalis extract has a synergistic effect with folic acid to induce hepatorenal injury. Natural extracts of marine species should be used with caution as a component of medications or natural remedies.

Background: Thrombotic events and oxidative stress are major complications of certain ischemic disorders. The fight against these complications requires very intense research to develop new therapeutic agents of natural origin. Objective: The general objective of this work is the scientific valorization of five medicinal plants: Rhus pentaphylla, Zizyphus lotus, Ammodaucus leucotrichus, Inula viscosa, and Cinnamomum zeylanicum by exploring their effects on rat platelet aggregation, antioxidant potential and determining their phytochemical composition. Methodology: The aggregation test was monitored by stimulating isolated washed platelets suspension in the absence and presence of extracts. The antioxidant activity was conducted in vitro according to three methods: DPPH free radical scavenging activity, β-carotene bleaching test, and ferric reducing antioxidant power test. The quantitative determination of total polyphenols and flavonoids are determined respectively according to the Folin-Ciocalteu method and the colorimetric method with aluminum chloride. Results: The results obtained show that the aqueous extract of the fruits of Rhus pentaphylla and the aerial part of Inula viscosa, as well as the stalk peel of Cinnamomum zeylanicum, significantly (p<0.001) inhibit thrombin-platelet aggregation, while the other plant extracts have a slightly, but significant effect. These extracts exert a remarkable antioxidant activity with the three methods used. But, their IC50 values are still higher than those of the antioxidant references (ascorbic acid and butyl hydroxyanisole). Qualitative phytochemical analysis revealed the presence of secondary metabolites with varying contents. Additionally, the results of quantitative phytochemical analysis showed that the aqueous extracts of the leaves of Rhus pentaphylla and the aerial part of Inula viscosa contain the highest amount of polyphenols and flavonoids. These secondary metabolites are also present in the other extracts but in smaller quantities. Conclusion: These results could contribute to the validation of the medical use of these extracts that exert an antiplatelet effect to treat hemostatic and thrombotic disorders.

Background: Drug resistance is an important phenomenon in helminth parasites. Microtubules are among the key chemotherapeutic targets, mutations of which lead to drug resistance. Objectives: The present study investigated the role of F167Y, E198A, and F200Y mutations in β- tubulin protein and their effect on albendazole binding. Methods: Brugia malayi β-tubulin protein models were generated using the SwissModel platform by submitting amino acid sequences. Mutations were carried out at amino acid sequences by changing F167Y, E198A, and F200Y. All the model proteins (one wild and three mutated) were docked with the anthelmintic drug albendazole using AutoDock vina-1.1.5. Docking complexes were further investigated for their binding stability by a Molecular Dynamic Simulation study using Gromacs-2023.2. The binding free energies of protein-ligand complexes were analyzed using the MM/PBSA package. Results: The docking study observed decreased ligand binding affinity in F167Y and E198A mutant proteins compared to wild proteins. MD simulation revealed the overall structural stability of the protein complexes during the simulation period. The simulation also observed more stable binding of albendazole in the active pocket of mutant proteins compared to wild-type proteins. Like ligand RMSD, wild-type protein also showed higher amino acid residual flexibility. The flexibility indicates the less compactness of wild β-tubulin protein complexes compared to mutant proteinligand complexes. Van der Waals and electrostatic interactions were found to be the major energy in protein-ligand complexes. However, due to higher solvation energy, wild-type protein showed more flexibility compared to others. Conclusion: The study, therefore, concludes that mutations at positions 167 and 198 of the β- tubulin protein contribute to resistance to albendazole through weakened binding affinity. However, the binding of albendazole binding to the proteins leads to structures becoming more stable and compact.